Project Summary/Abstract Age-related macular degeneration (AMD) is a complex disease with both genetic and environmental components contributing to personal risk. Common and rare variations in the complement and other pathways play a large role in the etiology of the disease, but the functional effects of most of these variants are not known. Rare variants in the complement pathway have stronger impact on the disease compared to common variants and can have clear biologic effects. Further investigation is required to reveal the functional effects of these rare variants and their phenotypic manifestations in this disease. The goals of this proposal are to better understand the impact of rare variants, especially in the complement pathway, through: 1) rigorous structural and functional analyses that will provide molecular insight into the pathophysiology of AMD; 2) genotype- phenotype evaluation of clinically detectible sub-phenotypes utilizing multimodal imaging to pinpoint differences between patients with and without rare variants; and 3) identification of additional novel rare variants using next generation sequencing, which will then be evaluated for their functional and phenotypic consequences. This collaborative effort will leverage a large and well characterized clinical study cohort, a state of the art complement analysis laboratory, and a world renowned genetics facility. Functional studies combined with genotype-phenotype analyses and discovery of novel genetic variants will expand knowledge of the pathological processes related to AMD, may reveal high risk subtypes of the disease that impact disease management, and will provide new targets for therapies.